Inherited neurodegenerative conditions have been identified in organisms as diverse as nematodes and man, but relatively little is understood about the genes involved and the mechanisms whereby mutant alleles induce inappropriate cell death. We study members of a family of genes, called degenerins, which can mutate to induce late onset swelling and necrotic- like death of specific groups of neurons in the easily studied nematode Caenorhabditis elegans. The degenerin gene family was originally defined by unusual dominant "killer" alleles of the mec4 and deg-I genes. Three degenerin-related genes from the rat, alpha-, beta-, and gamma rENaC, have been demonstrated to encode subunits of the amiloride-sensitive epithelial Na+ channel. We have speculated that the C. elegans degenerins mec-4 and mec-10 encode components of a mechanosensory ion channel, an exciting working hypothesis because eukaryotic mechanosensory channel components have not previously been isolated and the molecular properties of these channels are unknown. Our experiments indicate that ineffective channel closing is the critical event in the initiation of neurodegeneration. My long term research plan is to decipher in molecular detail how misregulation of ion channel activity (and other insults) induce necrotic- like death and to define the molecular events that transpire during neurodegeneration. Experiments outlined in this proposal are designed to enable us to describe how degeneration is initiated, what proteins are needed to enact the death, and even how cell corpses are removed. In addition, we will define distinctions/common features between degenerative cell death and the programmed cell death pathway (which we now believe overlap more than we originally anticipated). Finally, we expect to exploit the ability of mec4(d) to act as a killer gene to create ablation vectors and to set up a model system for studying degenerin-induced death in mammalian cell culture. Specifically, we will: l) assay the activities of wild-type and mutant channels in a oocyte expression system, 2) conduct genetic suppressor screens to identify genes essential for mec4(d)-induced neurodegeneration, 3) define effects of programmed cell death genes on touch cell degeneration, and 4) determine whether mec4(d) and potentially lethal variants of degenerin-related genes can induce degeneration in heterologous systems, develop ablation vectors which depend on the toxicity of these genes, and set up a mammalian culture model for degenerin-induced death. The proposed work is important to heath related issues in that it will advance understanding of degenerative cell death mechanisms and may inspire novel strategies for the prevention of injury-induced cell death. In addition, these studies will contribute to the characterization of a new ion channel class with a likely function in mechanotransduction a phenomenon which contributes to senses of touch, hearing and balance and more.